225 Desmoglein 1 deficiency in knockout mice impairs epidermal barrier formation and results in a psoriasis-like gene signature in E18.5 embryos

Abstract

Desmoglein 1 (Dsg1) is a desmosomal cadherin expressed in concert with a commitment to stratify and differentiate in multi-layered tissues. Its importance in epidermal function is underscored by human diseases such as SAM syndrome (Severe Skin Dermatitis, Allergies and Metabolic Wasting), caused by loss of function mutations. Dsg1 promotes differentiation and normal epidermal morphogenesis in human 3D epidermal models. To determine the systemic response to loss of Dsg1, we deleted the three, tandem a, b, and g genes in the mouse cadherin cluster using CRISPR/Cas9. Dsg1 knockout (KO) mice exhibit barrier impairment accompanied by peeling, denuded skin, and postnatal lethality. The basal desmosomal cadherin, desmoglein 3, is upregulated in Dsg1 KO skin, while differentiation associated proteins loricrin and filaggrin are decreased. Disrupted ZO1 localization, increased TEWL, and increased dye penetration are consistent with a defect in barrier formation. Whole transcriptome analysis of E18.5 skin was consistent with the observed alteration in differentiation and barrier formation, but also revealed an increase in pathways linked to psoriatic processes, including IL-17 signaling, MAPK activity, and ErbB signaling. There was significant overlap between the top 100 genes increased in human psoriasis lesions and genes increased in E18.5 Dsg1 KO animals. These data not only support an important role for Dsg1 in epidermal differentiation and barrier formation, they identify a potential role for Dsg1 in regulating inflammatory responses, with loss of Dsg1 in mouse embryo skin activating inflammatory pathways similar to those observed in patients with psoriasis.